Adv Ther (2013) 30:1067–1085 DOI 10.1007/s12325-013-0071-y
REVIEW
The Dipeptidyl Peptidase (DPP)-4 Inhibitors for Type 2 Diabetes Mellitus in Challenging Patient Groups David Kountz
To view enhanced content go to www.advancesintherapy.com Received: August 9, 2013 / Published online: November 28, 2013 Ó The Author(s) 2013. This article is published with open access at Springerlink.com
ABSTRACT
groups and have demonstrated significant
Treating hyperglycemia is a critical aspect of
improvements in measures of hyperglycemia, with a good safety profile. Based on the current
managing type 2 diabetes mellitus (T2DM), but
evidence, it appears that the DPP-4 inhibitors
can be especially challenging in patients from vulnerable groups such as those with chronic
are worthy of consideration not only for the most straightforward patients with T2DM, but
kidney disease, African Americans, and older people. The dipeptidyl peptidase (DPP)-4
also for these vulnerable patients.
inhibitors are relatively new oral antidiabetes drugs that have been incorporated into treatment algorithms over the past few years and have also been studied in these vulnerable patients. Clinical trials with DPP-4 inhibitors have now been reported for all these patient Electronic supplementary material The online version of this article (doi:10.1007/s12325-013-0071-y) contains supplementary material, which is available to authorized users. D. Kountz (&) Jersey Shore University Medical Center, RutgersRobert Wood Johnson Medical School, 1945 State Route 33, PO Box 397, Neptune, NJ 07754-0397, USA e-mail:
[email protected]
Keywords: African American; Chronic kidney disease; Dipeptidyl peptidase-4 Elderly; Type 2 diabetes mellitus
inhibitors;
INTRODUCTION The prevalence and incidence of diabetes are increasing worldwide, largely due to changing lifestyles characterized by reduced physical activity, rising obesity rates, and an aging population. In the US, diabetes is the leading cause of kidney failure, new cases of blindness, and non-traumatic lower limb amputations, and is a major cause of heart disease and stroke [1]. Diabetes currently affects 8.3% of the US population, some 25.8 million people [1], and type 2 diabetes mellitus (T2DM)
Enhanced content for Advances in Therapy articles is available on the journal web site: www.advancesintherapy.com
accounts for about 90–95% of all diagnosed diabetes cases in adults.
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Adv Ther (2013) 30:1067–1085
1068
It is well documented that good glycemic
extensive testing in phase 3 clinical trials, these
control can positively influence much of the
agents have now been included in treatment
morbidity and mortality associated with T2DM [2]. To manage hyperglycemia, expert
recommendations in all major diabetes guidelines. This review will provide a brief
guidelines recommend treatment to a glycated hemoglobin (HbA1c) level of below 6.5% or
overview regarding the positioning of DPP-4 inhibitors in the context of major clinical
below 7.0%, with recognition of the need for
guidelines. Furthermore, since the majority of
individualization of treatment example, to minimize the
for of
patients in phase 3 trials are relatively young and healthy, an additional objective of this review is
hypoglycemia [2–4]. The percentage of US individuals with self-reported diabetes who
to consider the DPP-4 inhibitors for the treatment of T2DM in more vulnerable patient populations,
achieved an HbA1c level of \7% increased
namely those with chronic kidney disease (CKD),
from 44% in 1988–1994 to 52.5% in 2007–2010 [5]. Similarly, an observational
African Americans, and older people. Current guidelines for these patients, and the clinical trials
study of non-insulin–treated patients with T2DM from Spain (n = 2,266) indicated that
conducted with DPP-4 inhibitors in these groups, will be reviewed.
goals, risks
45% had suboptimal HbA1c based on the \7% criterion [6]. The International Diabetes Management Practices Study (IDMPS) of data
METHODS
from developing regions of Eastern Europe, Asia, and Latin America reported that 36.4% of
This was a non-systematic review of the
participants with T2DM achieved an HbA1c of \7% [7]. These data were consistent with those from an observational study in Taiwan in which the percentage of patients achieving the \7% goal increased from 32.4% in 2006 to 34.5% in 2011 [8]. Taken together, these findings suggest that there has been some success in putting guidelines into practice, but that approximately one-third to one-half of patients still fail to achieve HbA1c levels below 7.0% [5–8]. Furthermore, the progressive deterioration of b-cell function, irrespective of pharmacological interventions to treat hyperglycemia, leads to
literature. A search of English-language literature was performed using PubMed and without imposing any time limitations. Search terms included combinations of the following: ‘type 2 diabetes’, ‘DPP-4 inhibitors’, ‘chronic kidney disease’, ‘end-stage renal disease’, ‘renal impairment’, ‘African American’, and ‘elderly’. Articles and abstracts relevant to the subject were included. Bibliographies from retrieved articles were also searched for relevant articles. Additional references known to the author were also included. The analysis in this article is based on previously conducted studies, and does not involve any new studies of human or animal
an almost inevitable need for intensification of treatment [2]. There is, therefore, a recognized
subjects performed by any of the authors.
need for new therapeutic options that are well tolerated over the long term and have a durable
DPP-4 INHIBITORS
effect.
The DPP-4 inhibitors improve glycemic control mainly via potentiation of the incretin effect,
The dipeptidyl peptidase (DPP)-4 inhibitors are relatively new drugs that may help meet the need for these types of treatments, and following
123
that is, the postprandial augmentation of insulin secretion by the gastrointestinal
Adv Ther (2013) 30:1067–1085
1069
incretin hormones glucagon-like peptide (GLP)-
associated with a low risk of hypoglycemia, and
1 and gastric inhibitory polypeptide (GIP).
have a favorable weight profile [11]. As evidence
Increases in GLP-1 levels appear to account for the majority of the DPP-4 inhibitors’ effects [9].
accumulates for their effectiveness, the DPP-4 inhibitors have been incorporated into
In addition to enhancing glucose-dependent insulin secretion, GLP-1 suppresses glucose-
numerous guidelines available for the management of patients with T2DM. A
dependent glucagon secretion, inhibits gastric
consensus statement and algorithm issued by
emptying, and reduces appetite and food intake [10]. It has long been known that the incretin
the American Association of Clinical Endocrinologists (AACE) in 2013 describes
effect is blunted in patients with T2DM, generating interest in therapies that target the
several options for monotherapy and variations of combination therapy [4]. The
incretin system [10]. Native GLP-1 itself cannot
DPP-4
be used in therapy due to its rapid degradation by the DPP-4 enzyme, resulting in a half-life of
monotherapy options for patients with an entry level HbA1c of \7.5%. As with American
less than 2 min. Nevertheless, therapeutic approaches for enhancing incretin action have
Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD)
been
degradation-
recommendations, metformin is recommended
receptor agonists, and of GLP-1 indirectly by
as the first-line choice where not contraindicated. The AACE algorithm also
inhibition of DPP-4 [10]. Four DPP-4 inhibitors are approved in the
places DPP-4 inhibitors as an option for the second component of initial dual or triple
US: sitagliptin (approved 2006), saxagliptin (approved 2009), linagliptin (approved 2011),
therapy in patients with entry HbA1c levels of C7.5% or C9%, respectively. The DPP-4
and alogliptin (approved 2013). Vildagliptin is
inhibitors may also be considered as the first
another DPP-4 inhibitor that has been extensively studied and is currently available
component of dual or triple therapy for patients for whom metformin is contraindicated. The
in the European Union and Japan. There are also other DPP-4 inhibitors in earlier stages of
detailed AACE guidelines issued in 2011 noted that DPP-4 inhibitors, along with metformin,
development that may become available over
sulfonylureas, glinides, and thiazolidinediones,
the coming years. Although all of the DPP-4 inhibitors share the same mechanism of action,
are all approved for use in combination with insulin [3]. However, the guidelines also
they have different chemical pharmacokinetic properties, which
and may
highlight a raised potential for hypoglycemia when a sulfonylurea or a glinide is used with
translate into clinical options with distinct
insulin, as well as several adverse effects
profiles.
associated with thiazolidinediones in combination with insulin, suggesting that
Place in Current Guidelines
these combinations considered.
developed
resistant GLP-1 increasing levels
and
include
In clinical trials, all available DPP-4 inhibitors have been shown to improve glycemic control,
inhibitors
are
placed
should
be
among
carefully
The ADA and EASD also issued a position
with clinically meaningful reductions in HbA1c
statement on the management of hyperglycemia in T2DM [12]. The ADA/EASD
[11]. Furthermore, they are well tolerated, are
guidelines
are
less
prescriptive,
discuss
123
Adv Ther (2013) 30:1067–1085
1070
advantages
and
disadvantages
of
all
Use in Patients with Chronic Kidney Disease
antidiabetes medicines, and highlight the need for individualization of treatment. In the general recommendations outlined in the guidelines, DPP-4 inhibitors are positioned alongside sulfonylureas, thiazolidinediones, GLP-1 agonists, and insulin, as a second-line add-on to metformin. They are prioritized along with GLP-1 agonists as an add-on to metformin when the goal is to avoid weight gain, and with GLP-1 agonists and thiazolidinediones when the goal is to avoid hypoglycemia. When metformin is not an option for first-line therapy, the ADA/EASD guidelines suggest a
The National Kidney Foundation (NKF) Kidney Disease Outcomes Quality Initiative (KDOQI) defines CKD by the presence of kidney damage or a glomerular filtration rate (GFR) \60 mL/ min/1.73 m2 for 3 months or more [18]. It also classifies the stages of CKD as ranging between Stage 1 (kidney damage with normal or increased GFR) and Stage 5 (kidney failure). End-stage renal disease (ESRD) is included under Stage 5 of the KDOQI classification and is defined as irreversible decline in kidney
DPP-4
function that is severe enough to be fatal in the absence of dialysis or transplantation
Among other guidelines, the International
[18]. Diabetes is considered a major risk factor for
sulfonylurea, thiazolidinedione, inhibitor, or GLP-1 agonist.
Diabetes Federation [13], the National Institute for Health and Clinical Excellence [14], and the US Department of Veterans Affairs/Department of Defense [15], all suggest DPP-4 inhibitors as an alternative add-on to metformin, when a sulfonylurea is contraindicated or when hypoglycemia is a concern. Guidelines are typically based on randomized trials that recruit the most straightforward patients. In the past, this is known to have led to underuse of new treatments in the very patients who could benefit the most. For example, African Americans are generally not well represented in clinical trials [16], and this, in addition to other factors, resulted in lower use of angiotensin-converting
enzyme
(ACE)-
inhibitors (ACEI) for the treatment of hypertension in African Americans [17]. Conversely, therapies should not be used in patients when evidence is lacking. Therefore, in light of a number of recently reported studies, it is worthwhile examining the available evidence for use of DPP-4 inhibitors in vulnerable patient groups.
123
CKD, with nearly 40% of adults with T2DM having some degree of CKD [19, 20]. Furthermore, 44% of new ESRD cases in the US in 2010 had a primary diagnosis of diabetes [21]. While managing hyperglycemia is a key goal in patients with CKD, glycemic targets and choice of therapy in this patient group warrant special consideration. For example, metformin, normally the first choice of treatment for T2DM, is renally excreted, and decreased kidney function may increase the risk of lactic acidosis with its use. Current prescribing guidelines in the US contraindicate metformin when serum creatinine levels are C1.4 mg/dL in women and C1.5 mg/dL in men [22]. Furthermore,
many
other
common
antidiabetes drugs are renally excreted and have a prolonged half-life in patients with CKD, thereby increasing the risk of hypoglycemia. Recent guidelines for diabetes and CKD state that HbA1c targets of \7.0% are not recommended in patients with diabetes who are at risk for hypoglycemia, including those treated with insulin or sulfonylureas and/ or who have advanced CKD. They suggest
Adv Ther (2013) 30:1067–1085
1071
instead extending HbA1c targets above 7.0% for
the
patients with diabetes who are at risk of
mediated
hypoglycemia and have clinically significant comorbidities or limited life expectancy [23].
intestinal transport system and related to cytochrome P450 3A4 (CYP3A4) metabolism
The glucose-dependent stimulation of insulin release by the DPP-4 inhibitors confers
have been well characterized, with some variation among the DPP-4 inhibitors [37–41,
a low risk of hypoglycemia [24], suggesting
44]. Generally, the DPP-4 inhibitors have
potential value for managing hyperglycemia in patients with T2DM and CKD. Indeed, a
limited drug–drug interactions via these mechanisms [37–41, 44]. However, alternatives
number of trials that specifically investigated DPP-4 inhibitors in renally impaired
to strong inducers of CYP3A4 or P-gp (e.g. rifampin) are strongly recommended when
populations have been reported (Table 1) or
linagliptin is to be administered [38]. In
completed with results anticipated in the near future (Table 2) [25–36]. Efficacy and safety data
addition, a reduction of the saxagliptin dosage to 2.5 mg once daily is recommended when
from the clinical trials reported to date are encouraging, and the DPP-4 inhibitors were
coadministered with strong inhibitors (e.g. ketoconazole) [39].
generally
well
tolerated
(Table 1).
propensity via
for the
drug–drug
interactions
p-glycoprotein
(P-gp)
CYP3A4/5
With
appropriate caution, the DPP-4 inhibitors can be used in patients with all degrees of renal
Use in African Americans
insufficiency, including ESRD, although dosage reduction is needed for saxagliptin, sitagliptin,
African Americans are at an increased risk of T2DM, with a prevalence of diabetes
and vildagliptin. Linagliptin can be used without adjustment, since it is not renally
approximately double that of the white population [45]. This group also has an
excreted (Table 3) [37–41].
increased rate of complications and greater disability from complications, as well as poorer
Individuals with concomitant T2DM and CKD may be receiving an ACEI for
glycemic control and quality of care [46–50].
management of hypertension because this class of medications may reduce cardiovascular
The pathophysiology of T2DM may be different in African Americans than in other populations,
events and protect the kidney [2]. A small
with studies suggesting that insulin resistance is higher in minority populations [51]. There are
increase in the risk of angioedema has been observed in patients taking concurrent ACEI
various theoretical reasons to consider DPP-4
and vildagliptin, but the authors were unable to determine a class effect through review of
inhibitors in African Americans. First, a small number of studies report racial disparities in
postmarketing
GLP-1 levels that may have implications for efficacy of DPP-4 inhibitors in African
surveillance
data
and
the
literature [42]. It is postulated that ACE inhibition shifts the metabolism of the
Americans. Two studies observed that African
angioedema-associated vasoactive peptides bradykinin and substance P to the secondary
American adolescents had lower GLP-1 concentrations than white adolescents [52, 53].
DPP-4
In contrast, an earlier investigation reported that obese African American adults had
pathway
[42,
43].
However,
little
information is available regarding the clinical relevance and frequency of ACEI and DPP-4 inhibitor interactions [43]. On the other hand,
significantly higher fasting and post-challenge GLP-1 concentrations than obese white adults
123
123
Linagliptin, 5 mg/day
Saxagliptin, 2.5 mg/day
Sitagliptin, 50 mg/day (moderate RI) or 25 mg/day (severe RI)
Sitagliptin, 50 mg/day (moderate RI) or 25 mg/day (severe RI)
Sitagliptin, 25 mg/day
Vildagliptin, 50 mg/day
[29]
[30, 31]
[32]
[33]
[34]
[35, 36]
515 (Ext: 369)
54-week double-blind, randomized, parallel group 24-week double-blind, randomized, placebocontrolled phase; 28-week extension
Moderate/severec (controlled phase included four patients with ESRD on dialysis, two of these patients randomized to vildagliptin entered extension)
54-week double-blind, randomized, activecontrolled
12-week double-blind, randomized, placebocontrolled phase; 42-week activecontrolled extension
Continued (included insulin, insulin and OAD, OAD mono- and combination therapy)
All OADs washed out
Glipizide 2.5 mg/day; titrated to maximum of 20 mg/day Placebo
All OADs washed out
Glipizide 2.5 mg/day; titrated to maximum of 20 mg/day
Extension: glipizide 5 mg/ day; titrated in 2-week intervals to maximum of 20 mg/day
All OADs washed out; ?/insulin continued
Continued (included insulin, insulin and OAD, OAD monotherapy)
Placebo
First phase: placebo
Continued (included insulin, insulin and OAD, OAD mono- and combination therapy; fixed for 12 weeks, adjusted thereafter)
Placebo
52-week double-blind, randomized, placebocontrolled
12-week double-blind, randomized, placebocontrolled phase; 40-week extension
Background therapy
Control
Study design
ESRD, all undergoing dialysis
Moderate/severe, not on dialysisb
426
129
Moderate/severe/ ESRD on dialysisc
Moderate/severe/ ESRD
Severe, not on dialysisb
RI inclusion criteria
91
(Ext: 129)
170
133
Na
Week 54, severe RI: vildagliptin -0.8; placebo -0.07
Week 54, moderate RI: vildagliptin -0.57; placebo -0.13
Week 24, severe RI: vildagliptin -0.91; placebo -0.32
Week 24, moderate RI: vildagliptin -0.74; placebo -0.24
Approximate adjusted mean change from baseline, %e
Week 54: sitagliptin -0.72 (-0.95, -0.48) glipizide -0.87 (-1.11, -0.63)
Mean change from baselined, % (95% CI)
Week 54: sitagliptin -0.8 (-0.9, -0.6) glipizide -0.6 (-0.8, -0.5)
Mean change from baselined, % (95% CI)
Week 54: sitagliptin -0.7 (-0.9, -0.4) Placebo/glipizide: -1.0 (-1.6, -0.3)
Week 12: sitagliptin -0.6 (-0.8, -0.4) Placebo -0.2 (-0.4, 0.1)
Mean change from baseline, % (95% CI)
Week 52: saxagliptin -1.08 (-1.37, -0.80) Placebo -0.36 (-0.63, -0.08)
Week 12: saxagliptin -0.86 (-1.08, -0.64) Placebo -0.44 (-0.66, -0.23)
Adjusted mean change from baseline, % (95% CI)
Week 52: linagliptin -0.71; placebo 0.01
Week 12: linagliptin -0.76; placebo -0.15
Adjusted mean change from baseline, %
Change in HbA1c (reported as in original publication)
b
a
RI renal impairment, HbA1c glycated hemoglobin, OAD oral antidiabetes drug, ext extension, ESRD end-stage renal disease, CI confidence interval N number of randomized participants Degree of RI categorized based on glomerular filtration rate estimated by the Modification of Diet in Renal Disease formula as moderate (C30 to \50 mL/min/1.73 m2) or severe (\30 mL/min/1.73 m2) c Degree of RI categorized based on creatinine clearance (CrCl) estimated by the Cockcroft-Gault formula as moderate (CrCl C30 to \50 mL/min), severe (CrCl; \30 mL/min, and not receiving dialysis), or ESRD (receiving dialysis) d Least squares mean change from baseline e Number in this table estimated from bar graph of adjusted mean change in HbA1c
Study drug
References
Table 1 Prospective phase 2/3 clinical trials of DPP-4 inhibitors in renally impaired patients (with published results)
1072 Adv Ther (2013) 30:1067–1085
NCT01098539
NCT01087502
NCT00740363
Albiglutide/sitagliptin
Linagliptin/placebo and glimepiride
Sitagliptin/placebo
25
241
507
Number enrolled
4-week, open-label, randomized, crossover
12-week, doubleblind, randomized, placebo-controlled phase; 40-week active-controlled extension
26-week, doubleblind, randomized, active-controlled
Design
Age C18 years
New onset diabetes patients with fasting plasma glucose 7–8 mmol/L, and/or 2-h plasma glucose 12–18 mmol/L after an oral glucose tolerance test OR patients already on OAD therapy, but with HbA1c C8.0% and B11.0%
Renal transplant recipient more than 1 year post-transplant with stable renal function and stable prednisolone dose for the last 3 months before inclusion
Age C18 years
BMI B45 kg/m2
HbA1c C7.0% and B10.0%
Patients with T2DM and with GFR \60 mL/min
Fasting C-peptide C0.8 ng/mL (C0.26 nmol/L)
BMI C20 and B45 kg/m2
HbA1c C7.0% and B10.0%
Inadequate glycemic control with diet and exercise, or metformin, thiazolidinediones, sulfonylurea, or any combination of these OADs
Patients with T2DM and RI
Key inclusion criteria
T2DM type 2 diabetes mellitus, RI renal impairment, HbA1c glycated hemoglobin, BMI body mass index, GFR glomerular filtration rate, OAD oral antidiabetes drug
ClinicalTrials identifier
Study drug/comparator
Table 2 Recently completed phase 3/4 trials of DPP-4 inhibitors in renally impaired patients
Adv Ther (2013) 30:1067–1085 1073
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Adv Ther (2013) 30:1067–1085
1074
Table 3 Recommended dosing of DPP-4 inhibitors in the presence of CKD
Alogliptin [37]
First approved Standard dose
Recommended dose in context of chronic kidney disease
US (2013)
CrCl C30 to \60 mL/min (moderate RI): 12.5 mg once daily
25 mg once daily
CrCl \30 mL/min (severe/ESRD): 6.25 mg once daily Linagliptin [38]
US (2011)
5 mg once daily
No dose adjustment required
Saxagliptin [39]
US (2009)
5 mg once daily
CrCl B50 mL/min (moderate/severe/ESRD): 2.5 mg once daily
Sitagliptin [40]
US (2006)
100 mg once daily CrCl C30 to \50 mL/min (moderate RI): 50 mg once daily CrCl \30 mL/min (severe/ESRD): 25 mg once daily
Vildagliptin [41] EU (2007)
50 mg twice daily
CrCl \50 mL/min (moderate/severe/ESRD): 50 mg once daily
CrCl creatinine clearance, ESRD end-stage renal disease, RI renal impairment [54]. Further studies are warranted to confirm racial differences in GLP-1 levels and to
information for this population. While the DPP-4 inhibitors seem theoretically
investigate any therapeutic implications.
appropriate for use in African Americans with
In the meantime, there are other reasons why DPP-4 inhibitors may be a good option for this
T2DM, this group is characterized by higher HbA1c levels than other populations [58]. With
population. A significant proportion of African Americans are overweight or obese, with the
predicted HbA1c reductions ranging between 0.4 and 1.0% with this class of drugs [11, 59],
prevalence of overweight and obesity combined
monotherapy would likely not be suitable for all
at 76.6% (69.9% in men, 82.1% in women), and the prevalence of obesity at 49.6% (38.8% in
patients, although larger reductions are expected in patients with higher baseline
men, 58.6% in women) [55]. Overweight and obesity are risk factors for insulin resistance, and
HbA1c [60]. Based on composite analyses of available
all guidelines therefore recommend losing
pharmacokinetic
weight for overweight or obese patients with T2DM [2–4]. In contrast to insulin and some oral
information for all DPP-4 inhibitors state that no dose adjustment is necessary based on race
antidiabetes drugs that can result in weight gain, the weight-neutral DPP-4 inhibitors may
[37–41], but to date only linagliptin has been specifically investigated in African Americans. A
therefore be an appropriate option for patients
phase 1 study (NCT00935220) assessing its
who are overweight or obese. African Americans are also disproportionally affected by CKD and
pharmacodynamic and pharmacokinetic profile in African Americans with T2DM for
ESRD [56, 57], with the rate of new ESRD cases being 3.4 times higher among this group than
7 days, supported linagliptin 5 mg/day as effective for controlling blood glucose levels
among the white population [21]. The presence
[61]. A subsequent phase 3 trial (NCT01194830)
of renal impairment has implications for diabetes management, but as discussed in the
evaluated its efficacy and safety in black/African Americans with T2DM over 24 weeks [62]. In
previous section, the DPP-4 inhibitors remain a viable choice in this setting.
this study, 226 patients were randomized to linagliptin or placebo, and HbA1c levels were
Despite the prevalence of T2DM in African Americans,
123
there
is
limited
clinical
trial
measured
every
data,
6 weeks.
the
A
prescribing
statistically
significant and clinically relevant difference
Adv Ther (2013) 30:1067–1085
1075
between treatment groups was found for the
range of 7.0–7.5% should generally be aimed for
change in HbA1c after 24 weeks [placebo-
in older patients. The caveat to this statement is
adjusted mean change of -0.58% (95% CI 0.91 to -0.26%; P\0.001)], indicating the
that individual comorbidities, and cognitive and functional status, should be considered
superiority of linagliptin compared with placebo in reducing HbA1c in black/African
when determining goals. Furthermore, this position statement highlights hypoglycemia in
American
as
older people as a highly prevalent and under-
expected from pivotal trials, linagliptin was well tolerated and weight neutral, with a low
recognized disorder with severe consequences such as falls, cognitive impairment, and
rate of hypoglycemic events, confirming its safety profile as well as efficacy in African
hospital admission [69]. The heterogeneity of this population is also
American patients with T2DM [63].
addressed
Use in Older People
recommend that the same glycemic targets be applied to otherwise healthy older people as to
The latest census figures in the US indicate that
younger people with diabetes; and a less ambitious target be applied to patients with
patients
[63].
Furthermore,
people aged 65 years and older represent 13.2% of the population [64], and this proportion is
by
the
ADA.
Their
guidelines
more complicated conditions that include
expected to grow to just over 20% by 2050 [65].
multiple comorbidities, a high level of functional dependency, and limited life
The incidence of T2DM in older people is a major public health concern, and in 2010
expectancy [2, 70]. The DPP-4 inhibitors
almost 27% of people aged 65 years and older in the US had diabetes [1]. Clinical
particular interest for the treatment of older patients with T2DM for a number of reasons,
management of the older patient with T2DM is often challenging as these patients have an
namely their convenient oral dosing, the
have
generated
increased prevalence of cardiovascular risk
importance of avoiding hypoglycemia in the elderly, and considerations of declining renal
factors, diabetes-related complications, and comorbidities such as renal impairment,
function in this patient group. Indeed, the recent position statement mentioned above
congestive heart failure, cognitive impairment, and physical disability. Furthermore, they are
states that in selected older patients not at
often prescribed multiple medications, which
target or where there is poor tolerance to glucose-lowering agents, the use of DPP-4
further complicates treatment strategies and may reduce adherence [66–68]. The older
inhibitors can be considered as second-line therapy [69]. The ADA acknowledges the few
T2DM patient population is, however, a highly heterogeneous group with a broad spectrum of
side effects associated with DPP-4 inhibitors in
and
the context of their use in older patients; however, it also notes that their costs may be
comorbidities. A position statement issued by the International Association of Gerontology
a barrier to some older patients [2]. The prescribing information available for these
and Geriatrics (IAGG), the European Diabetes Working Party for Older People (EDWPOP), and
drugs
disease
duration,
life
expectancy,
generally
agree
that
no
overall
the International Task Force of Experts in
differences in safety or effectiveness were observed between patients aged 65 years and
Diabetes, recommends that an HbA1c target
over and younger patients [37–41]. However,
123
Adv Ther (2013) 30:1067–1085
1076
caution is advised in the context of older
well tolerated in elderly patients and no safety
patients,
concerns were identified.
who
are
more
likely
to
have
decreased renal function, and dosing adjustments are recommended for all DPP-
Other pooled analyses, subgroup analyses, and systematic reviews also showed that DPP-4
inhibitors, except circumstances.
these
inhibitors in the older T2DM population were generally effective and well tolerated [74–81].
Three studies that prospectively assessed
However, some studies show that when DPP-4
DPP-4 inhibitors in older patients with T2DM have been reported [71–73] (Table 4). A double-
inhibitors are concomitantly administered with insulin or a sulfonylurea, there is an elevated
blind, randomized, active-controlled study compared vildagliptin with metformin over 24 weeks in 335 drug-naı¨ve patients with
risk of hypoglycemia over the concomitant administration of placebo with insulin or a
T2DM aged C65 years. In this study, 41% of patients had normal renal function, 57% had
analysis evaluating linagliptin as add-on therapy to basal insulin showed no increased
mild renal insufficiency, and less than 2% had moderate renal insufficiency. The investigation
risk of hypoglycemia with the DPP-4 inhibitor [81]. Given the serious consequences of
showed that vildagliptin is an effective and
hypoglycemic events in older patients, the
well-tolerated treatment option in this group, demonstrating non-inferiority to metformin in
combination of a DPP-4 inhibitor with a sulfonylurea is perhaps ill advised; in fact, the
terms of glycemic control, but superior gastrointestinal tolerability [71]. The second
IAGG, EDWPOP, and the International Task Force of Experts in Diabetes recommend that
trial, a double-blind, randomized, placebocontrolled study of sitagliptin over 24 weeks in
sulfonylurea therapy should be avoided in any older patient at risk of hypoglycemia [69].
linagliptin,
under
206 patients with T2DM aged C65 years,
sulfonylurea [82, 83]. In contrast, a pooled
Interestingly,
there
is
also
preliminary
concluded that sitagliptin significantly and rapidly improved glycemic control and was
evidence that DPP-4 inhibitors are associated with a reduced risk of bone fractures compared
well tolerated in this group [72]. This study also included patients with moderate renal
with placebo or other treatments [84]. Recent evidence shows that T2DM is an independent
insufficiency (22%), but excluded those with
risk factor for bone fracture [85, 86] and that
severe renal insufficiency (estimated creatinine clearance \35 mL/min). Finally, a randomized,
older people with T2DM are at an increased risk of hip fractures [87, 88]. Furthermore, clinical
double-blind, placebo-controlled study investigated the efficacy and safety of
trial data suggest that DPP-4 inhibitors may be associated with a lower risk of stroke compared
linagliptin in 241 patients aged C70 years with
with other therapies [89]. Patients with diabetes
T2DM and insufficient glycemic control despite metformin and/or sulfonylurea and/or insulin
have an increased risk of ischemic stroke, a risk that increases in correlation with duration of
therapy [73]. The majority of patients in this study had either normal renal function (21%) or
diabetes [90, 91], therefore posing a particular concern for elderly patients with long-standing
mild renal insufficiency (52%); 26% of patients
T2DM. If confirmed, these risk reductions will
had moderate renal insufficiency and less than 2% had severe renal insufficiency. This study
provide further compelling reasons to consider DPP-4 inhibitors in older patients. Various
concluded that linagliptin was effective and
prospective studies of glycemic outcomes in
123
Vildagliptin, 100 mg/day
Sitagliptin, 100 or 50 mg/day depending on renal function
Linagliptin
[71]
[72]
[73]
C70 yrs
C65 yrs
206
241
C65 yrs
Age inclusion criteria
335
Na
74.9 yrs
72 yrs
71 yrs
Mean age
24-week double-blind, randomized, placebocontrolled, parallel group study
24-week double-blind, randomized, placebocontrolled, parallel group study
24-week double-blind, randomized, activecontrolled, parallel group study
Study design
All OADs washed out
Continued (included metformin, sulfonylureas, or basal insulin, or combinations of these drugs)
Placebo
Patients considered drug-naı¨ve (no OADs for at least 12 weeks prior to screening; no OADs for more than 3 consecutive months at any time in the past)
Background therapy
Placebo
Metformin
Control
HbA1c glycated hemoglobin, yrs years, OAD oral antidiabetes drug, CI confidence interval a N number of randomized participants b Least squares mean change from baseline
Study drug
Ref
Table 4 Prospective phase 2/3 clinical trials of DPP-4 inhibitors in older patients (with published results)
Week 24: linagliptin -0.61 (0.06) Placebo 0.04 (0.07)
Adjusted mean change from baseline, % (SE)
Week 24: sitagliptin -0.5 (-0.7, -0.2) Placebo 0.2 (0.0, 0.5)
Mean change from baselineb, % (95% CI)
Week 24: vildagliptin -0.64 (0.07), (P \ 0.001 vs. baseline) Metformin -0.75 (0.07), (P \ 0.001 vs. baseline)
Adjusted mean change from baseline, % (SE)
Change in HbA1c (reported as in original publication)
Adv Ther (2013) 30:1067–1085 1077
123
123
NCT01006603 (completed)
NCT01183104 (recruiting)
NCT01189890 (completed)
NCT01257451 (completed)
Saxagliptin/ glimepiride
Sitagliptin/ glimepiride
Sitagliptin/ glimepiride
Vildagliptin/ placebo
431
480
900
957
March 2012
October 2012
December 2014
June 2012
24-week, doubleblind, randomized, placebo-controlled
30-week, doubleblind, randomized, active-controlled
52-week, open-label, randomized, activecontrolled
52-week, doubleblind, randomized, active-controlled
(Estimated) (Estimated) Study design number enrolled completion date
Patients with T2DM; HbA1c C7.0% and B10.0% and assessed as inadequately controlled; BMI C19 and B45 kg/m2; age C70 years
Patients with T2DM; community-dwelling; age 65–85 years
Patients with T2DM who are OAD-naı¨ve (or alphaglucosidase or biguanide monotherapy, to be washed out 4 weeks prior to randomization); treatment with diet and exercise for 12 weeks or longer at screening; HbA1c C6.9% and B8.9%; age C60 years
Patients with T2DM treated with stable metformin monotherapy for at least 8 weeks prior to first visit; HbA1c C7.0% and B9.0%; age C65 years
Key inclusion criteria
T2DM type 2 diabetes mellitus, HbA1c glycated hemoglobin, OAD oral antidiabetes drug, BMI body mass index
ClinicalTrials identifier
Study drug/ comparator
Table 5 Planned/recently completed prospective clinical trials of DPP-4 inhibitors in older patients
1078 Adv Ther (2013) 30:1067–1085
(TECOS)
NCT00790205
(SAVOR-TIMI 53) 14,000
7.7-year, double-blind, randomized, active controlled
December 2014 (ongoing)
Patients with T2DM; HbA1c C6.5%; high risk for cardiovascular events
Patients with T2DM; HbA1c C6.5% and B8.5% if treatment-naı¨ve or mono-/dual therapy with metformin and/or alpha-glucosidase inhibitor; HbA1c C6.5% and B7.5% if treatment with sulfonylurea/glinides in mono- or dual therapy with metformin and/or alpha-glucosidase inhibitor; pre-existing cardiovascular disease OR specified diabetes end-organ damage OR age C70 years OR C2 specified cardiovascular risk factors
Patients with T2DM who are drug-naı¨ve or receiving monotherapy or combination antidiabetes therapy; HbA1c C6.5% and B10.0%; high risk of cardiovascular events defined by: (1) albuminuria (UACR C30 mg/g) plus previous macrovascular disease and/or (2) impaired renal function patients with eGFR 15 to \45 mL/min/ 1.73 m2 are eligible with any UACR level, those with eGFR C45–75 mL/min/1.73 m2 are required to have a UACR [200 mg/g)a
4–5-year, double-blind, Patients with T2DM; HbA1c C6.5% and B8.0% on stable randomized, placebodose(s) of antihyperglycemic agent(s), including insulin; precontrolled existing cardiovascular disease
May 2013 4-year, double-blind, (completed) randomized, placebocontrolled
September 2018 (ongoing)
January 2018 4-year, double-blind, (recruiting) randomized, placebocontrolled
T2DM type 2 diabetes mellitus, HbA1c glycated hemoglobin, UACR urinary albumin creatinine ratio, eGFR estimated glomerular filtration rate a Additional study details from https://investor.lilly.com/releasedetail.cfm?ReleaseID=781539
Sitagliptin/ placebo
16,492
NCT01107886
Saxagliptin/ placebo
8,300
6,000
(CARMELINA)
NCT01897532
Linagliptin/ NCT01243424 glimepiride (CAROLINA)
Linagliptin/ placebo
(EXAMINE)
5,380
June 2013 4.75-year, double-blind, Patients with T2DM receiving monotherapy or combination (completed) randomized, placeboantidiabetes therapy; HbA1c C6.5% and B11.0%; HbA1c C7.0% controlled and B11.0% if on insulin; diagnosis of acute coronary syndrome within 15–90 days prior to randomization
NCT00968708
Key inclusion criteria
Alogliptin/ placebo
Study design
(Estimated) completion date
Study drug/ ClinicalTrials (Estimated) comparator identifier (NAME) number enrolled
Table 6 Completed or ongoing clinical trials to investigate effects of DPP-4 inhibitors on cardiovascular morbidity and mortality
Adv Ther (2013) 30:1067–1085 1079
123
Adv Ther (2013) 30:1067–1085
1080
this population are underway or recently
investigate the effects of DPP-4 inhibitors on
completed (Table 5), and their findings will
cardiovascular
provide further valuable safety and efficacy data about DPP-4 inhibitors in this group, and
(Table 6), and provide further insight into the efficacy, safety, and durability of response of
may also allow for additional pooled analyses of outcomes of interest such as fracture.
these drugs. Results from the first two completed trials, EXAMINE and SAVOR-TIMI
Furthermore, ongoing cardiovascular safety
53, demonstrated no change in the risk of the
trials with the DPP-4 inhibitors (see below and Table 6) are expected to include
composite major adverse cardiovascular event endpoint with either alogliptin or saxagliptin
substantial numbers of elderly patients, providing valuable outcome information in
compared with placebo when added to the standard of care [97, 98]. In EXAMINE, the
this
morbidity
and
mortality
particular,
point estimate for the hazard ratio (HR) was \1
patients aged C70 years qualify for inclusion in the CAROLINA (Cardiovascular Outcome
and the upper limit of the 95% CI was \1.3, which was the pre-specified non-inferiority
Study of Linagliptin Versus Glimepiride in Patients With Type 2 Diabetes) trial, a large-
safety margin (HR with alogliptin, 0.96; upper boundary of the one-sided repeated CI, 1.16;
scale study that aims to investigate the effects
P\0.001 for non-inferiority) [97]. Similarly in
of linagliptin on cardiovascular morbidity and mortality.
SAVOR-TIMI 53, saxagliptin met the noninferiority criterion but did not demonstrate
Future Directions
cardiovascular superiority versus placebo (HR with saxagliptin 1.00, 95% CI 0.89–1.12,
Safety data for DPP-4 inhibitors based on
P = 0.99 for superiority, P\0.001 for noninferiority) [98].
particular
population.
In
registration studies are reassuring, with various meta-analyses indicating a benign and perhaps beneficial cardiovascular safety profile
CONCLUSIONS
for the class [92–96]. However, their long-term impact on cardiovascular outcomes has yet to
The DPP-4 inhibitors are clearly emerging as a
be firmly established by clinical trials. To address this, several large-scale trials,
useful treatment option in the general T2DM population and, as additional trials are reported,
including
of
it appears their characteristics may make them
Cardiovascular Outcomes with Alogliptin versus Standard of Care), CARMELINA
particularly suitable for more vulnerable patient populations. DPP-4 inhibitors can be used in
(Cardiovascular and Renal Microvascular Outcome Study With Linagliptin in Patients
the context of CKD, a significant consideration for any antidiabetes treatment. They are also
With Type 2 Diabetes Mellitus at High Vascular
weight neutral, an important aspect when
Risk), CAROLINA, SAVOR-TIMI 53 (The Saxagliptin Assessment of Vascular Outcomes
making therapy choices with a patient who is overweight or obese. Furthermore, their
Recorded in Patients with Diabetes Mellitus— Thrombolysis in Myocardial Infarction 53
straightforward dosing and low risk of hypoglycemia are desirable characteristics,
trial), and TECOS (Sitagliptin Cardiovascular
particularly when choosing treatments for older patients.
Outcome
123
EXAMINE
Study),
have
(Examination
been
designed
to
Adv Ther (2013) 30:1067–1085
1081
For various reasons, physicians may be cautious
about
using
new
therapies
in
vulnerable patient populations. However, these groups could potentially benefit from new treatments, and caution can be balanced by close monitoring and vigilance to ensure
conducted studies, and does not involve any new studies of human or animal subjects performed by any of the authors. Open Access. This article is distributed
therapeutic
under the terms of the Creative Commons Attribution Noncommercial License which
advances. Given the variable progression of T2DM and the heterogeneity even within
permits any noncommercial use, distribution, and reproduction in any medium, provided the
subgroups of patients, individualizing therapy will always be essential. Nevertheless, awareness
original author(s) and the source are credited.
that
all
groups
benefit
from
of the typical issues for these high-risk groups may help physicians who are considering therapeutic options, including the DPP-4
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